MedGen

Fragile X-associated primary ovarian insufficiency (FXPOI) is a condition that affects women and is characterized by reduced function of the ovaries. The ovaries are the female reproductive organs in which egg cells are produced. As a form of primary ovarian insufficiency, FXPOI can cause irregular menstrual cycles, early menopause, an inability to have children (infertility), and elevated levels of a hormone known as follicle stimulating hormone (FSH). FSH is produced in both males and females and helps regulate the development of reproductive cells (eggs in females and sperm in males). In females, the level of FSH rises and falls, but overall it increases as a woman ages. In younger women, elevated levels may indicate early menopause and fertility problems.

The severity of FXPOI is variable. The most severely affected women have overt POI (formerly called premature ovarian failure). These women have irregular or absent menstrual periods and elevated FSH levels before age 40. Overt POI often causes infertility. Other women have occult POI; they have normal menstrual periods but reduced fertility, and they may have elevated levels of FSH (in which case, it is called biochemical POI). The reduction in ovarian function caused by FXPOI results in low levels of the hormone estrogen, which leads to many of the common signs and symptoms of menopause, such as hot flashes, insomnia, and thinning of the bones (osteoporosis). Women with FXPOI undergo menopause an average of 5 years earlier than women without the condition. [from MedlinePlus Genetics]

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]

Premature ovarian failure-2A (POF2A) is a defect of ovarian development and is characterized by primary or secondary amenorrhea, with elevated levels of serum gonadotropins, or by early menopause (Bione et al., 1998). Sala et al. (1997) and Bione et al. (1998) suggested that several genes in a region defined as POF2 (Xq13.3-q22) can influence ovary development and/or oogenesis. For a phenotypic description and a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure (POF), the endpoint of primary ovarian insufficiency, affects approximately 1% of women worldwide. Patients with POF present with at least a 6-month history of amenorrhea and elevated plasma levels of follicle-stimulating hormone (more than 40 mIU per milliliter). The disorder can result from premature depletion of the follicle pool, follicular atresia, follicle growth arrest, or ovarian dysgenesis (see 233300). In approximately 10 to 15% of patients with POF, a genetic cause has been determined (summary by Caburet et al., 2014). For general phenotypic information and a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-11 (POF11) is characterized by secondary amenorrhea and hypergonadotropic ovarian insufficiency, with elevated serum follicle-stimulating hormone (FSH; see 136530) levels before age 40 years (Qin et al., 2015). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-15 (POF15) is characterized by primary amenorrhea, oligomenorrhea, or secondary amenorrhea; small ovaries with reduced or absent follicles; and elevated gonadotropic hormones (Fouquet et al., 2017; Jaillard et al., 2020; Heddar et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-10 (POF10) represents a syndrome characterized by primary amenorrhea, hypergonadotropic ovarian insufficiency, and genomic instability in somatic cells. For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). For a discussion of genetic heterogeneity of age at natural menopause, see MENOQ1 (300488). [from OMIM]

Nonsyndromic primary ovarian insufficiency, which is characterized by amenorrhea with elevated gonadotropin levels, is observed in 1% of otherwise healthy women under the age of 40 years (summary by Wang et al., 2014). For a general phenotypic description and discussion of the genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-17 (POF17) is characterized by early cessation of menses after initial menarche, with small ovaries and uterus (Zhang et al., 2019). For a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-14 (POF14) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels (Franca et al., 2018). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-22 (POF22) is characterized by female infertility, with small to atrophic ovaries and no visible ovarian follicles (Wu et al., 2022; Zhang et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-23 (POF23) is characterized by female infertility due to reduction of ovarian reserve. After normal menarche, patients experience oligomenorrhea and secondary amenorrhea (Caburet et al., 2019). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-20 (POF20) is characterized by female infertility due to secondary amenorrhea. Some patients exhibit atrophic ovaries lacking follicles (Carlosama et al., 2017; Akbari et al., 2021; Wyrwoll et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of POF, see POF1 (311360). [from OMIM]

Premature ovarian failure-21 (POF21) is characterized by female infertility due to primary or secondary amenorrhea. Ovaries are small, atrophic, or nonvisualized on ultrasound (Tucker et al., 2019; Tucker et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of POF, see POF1 (311360). [from OMIM]

Premature ovarian failure-25 (POF25) is an autosomal recessive disorder characterized by irregular menses followed by early menopause. Ovaries appear atrophic on ultrasound, with few to no follicles (Yao et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-24 (POF24) is characterized by the development of secondary amenorrhea in the fourth decade of life, with a dearth of antral follicles detected on ultrasound. Patients may experience subfertility or infertility (He et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-18 (POF18) is characterized by irregular menstrual cycles and cessation of menstruation in the third decade of life. The uterus is small; ovaries may be small or rudimentary, and do not show follicular activity (Fan et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-13 (POF13) is characterized by female infertility due to secondary amenorrhea in the third decade of life. Patients exhibit atrophic ovaries devoid of follicles (Guo et al., 2017). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]

Premature ovarian failure-19 (POF19) is characterized by irregular menses that cease in the third decade of life, associated with infertility (Felipe-Medina et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360). [from OMIM]